Citokynes Responses
CI reveal a differential response on the cytokine and chemokine levels (ROSSEAU et al., 2007) * Elevated intrapulmonary levels of inflammatory cytokines were observed in mice inoculated with CI with an interval of 2 days (METERSKY et al., 2012). * Reduced number of lung effector cells in coinfected animals was associated with reduction in cytokine production in surviving cells (BLEVINS et al., 2014). * Reduced cytokine production was directly correlated with a decrease in the level of mRNA (BLEVINS et al., 2014). Interleukin IL-1 => Monocytes are the main source of secreted IL1. They express predominantly IL1-beta while human keratinocytes express large amounts of IL1-alpha. * Elevated concentrations of IL-1Beta levels in the lung, indicative of enhancedneutrophil activity(BLOK et al., 2013). IL-6 * Elevated concentrations of IL-6 levels in the lung, indicative of enhanced neutrophil activity (BLOK et al., 2013). IL-10 * In IV–infected hosts, expression of inhibitory IL-10 induced by 2,3-dioxygenase, has been reported to be partially responsible for the increased susceptibility to secondary bacterial infection, likely due to an effect on neutrophil function (METZGER; SUN, 2013). * Elevated concentrations of IL-10 levels in the lung, indicative of enhanced neutrophil activity (BLOK et al., 2013). * Pulmonary interleukin-10 levels were increased in coinfected mice infected with IV for 6 days but not 3 days (MCNAMEE;HARMSEN, 2006). * 50-fold higher pulmonary levels of IL-10 were observed in IV-recovered mice than in control mice (VAN DER SLUIJS et al., 2004). * Treatment with an anti-IL-10 mAb 1h before bacterial inoculation resulted in reduced bacterial outgrowth and reduced lethality during secondary bacterial pneumonia compared with those in control mice (VAN DER SLUIJS et al., 2004). * The increased susceptibility to secondary bacterial pneumonia is at least in part caused by excessive IL-10 production (VAN DER SLUIJS et al., 2004). IL-17 * Mice deficient in type I IFN receptor (IFNAR knockout mice) demonstrated an enhanced innate expression of IL-17 relative to WT mice (LI; MOLTEDO; MORAN, 2012). IL-22 * IL-22, as well as factors associated with its production, are expressed in the lung tissue during the early phases of IAV infection (IVANOV et al., 2013). * During sub-lethal IAV infection, IL-22-deficient animals had enhanced lung injuries and showed a lower airway epithelial integrity relative to WT littermates (IVANOV et al., 2013). * The protective effect of endogenous IL-22 in pulmonary damages was associated with a more controlled secondary bacterial infection (IVANOV et al., 2013). * After challenge with SP, IAV-experienced IL22-/- animals were more susceptible than WT controls in terms of survival rate and bacterial burden in the lungs (IVANOV et al., 2013). IL-27 * IV infection induced pulmonary IL-27 production in a type I IFN-a/b receptor (IFNAR) signaling-dependent manner, which sensitized mice to secondary SP infection downstream of IFNAR pathway (CAO et al., 2014) IL-33 * Elevated concentrations of IL-33 levels in the lung, indicative of enhancedneutrophil activity(BLOK et al., 2013). Tumor necrosis factors TNF-α * TNF-a production is decreased in animals previously infected with IV, even in the presence of IFN-g. This is probably related to the finding that IV infection leads to desensitization of TLR4-mediated signaling.(METZGER; SUN, 2013). Interferon => Interferons are proteins that, at least in homologous cells, elicit a virus-unspecific antiviral activity. Type I IFN => IFN-alpha, IFN-beta (humans), IFN-omega, IFN-delta, IFN-epsilon, IFN-kappa. * Synergistic stimulation of type I IFN production leads to increased bacterial colonization (NAKAMURA; DAVIS; WEISER, 2011). * Co-induction of type I IFN by IV and pneumolysin-expressing SP signaling through Nod2 attenuates the CCL2 response and blocks the AM recruitment that is necessary to clear SP colonization (LIJEK; WEISER, 2013). * Type I IFN expression was induced by SP colonization alone (NAKAMURA; DAVIS; WEISER, 2011). * IV-induced type I IFNs sensitize hosts to secondary bacterial infections (SHAHANGIAN et al., 2009). * IV-infected mice deficient for type I IFN-α/β receptor signaling (IFNAR knockout mice) had improved survival and clearance of secondary SP infection from the lungs and blood. This indicates the great importance of the type I IFN inhibitory pathway on CXC chemokine production (SHAHANGIAN et al., 2009). * The induction of type I IFNs during a primary nonlethal IV infection is sufficient to promote a deadly SP secondary infection (LI; MOLTEDO;MORAN, 2012). * Mice deficient in type I IFN receptor (IFNAR knockout mice) effectively cleared the secondary bacterial infection from their lungs, increased the recruitment of neutrophils, and demonstrated an enhanced innate expression of IL-17 relative to WT mice (LI; MOLTEDO; MORAN, 2012). * IFN-I plays an important role in the host defense against SP by counteracting the transmigration of bacteria from the lung to the blood (LEMESSURIER et al., 2013). * IFN-I regulates two possible mechanisms involved in SP invasion: PAF receptor-mediated transcytosis and tight junction-dependent pericellular migration, ultimately limiting progression from a site-restricted lung infection to invasive, lethal disease (LEMESSURIER et al., 2013). * Type I IFNs signal through a common receptor, IFN-α/β receptor (IFNAR), resulting in the expression of pro-inflammatory genes that not only inhibit viral replication, but also augment various aspects of adaptive immunity (SHAHANGIAN et al., 2009). * Mice deficient for TLR2 showed decreased expression of IFN-α (RICHARD et al., 2014). Type II IFN * Susceptibility to secondary bacterial infection was decreased in the absence of type II, but not type I, IFN signaling (SUN et al., 2011). IFN-γ => IFN-γ is produced mainly by T-cells and NK cells activated by antigens. It is produced by lymphocytes expressing the surface antigens CD4 and CD8. * The increased susceptibility to bacterial infection was correlated with augmented IFN-γ production produced during the recovery stage of IAV infection (SUN et al., 2011). * Bacterial lung loads were higher in st22/2 mice during the later stages of secondary SP pneumonia, which was associated with relatively increased lung IFN-γ levels (BLOK et al., 2013). * IFN-γ suppresses innate protection against extracellular bacterial pathogens in the lung, although probably facilitates induction of specific anti-IV adaptive immunity (SUN; METZGER, 2008). * Direct inoculation of IFN-γ can mimic IV infection and downregulate the expression of the class A scavenger receptor MARCO on AMs (SUN; METZGER, 2008). * The increase of IFN-γ caused by adaptive immune response to IV infection downregulates the AM receptors with collagenous structure (MARCO) that are involved in phagocytosis of unopsonized SP (CHIEN, 2011). * Cells that retained the ability to produce IFN-γ exhibited a decreased potential for coproduction of TNF-α (BLEVINS et al., 2014). * Production of IFN-γ after IV infection alters the activation status of local AMs, allowing them to enhance adaptive antiviral responses through increased MHC expression while repressing their ability to mediate innate immunity (SUN; METZGER, 2008), Chemokines Elevated intrapulmonary levels of inflammatory chemokines were observed in mice inoculated with CI with an interval of 2 days (METERSKY et al., 2012). KC * Elevated concentrations of keratinocyte-derived chemokine levels in the lung, indicative of enhanced neutrophil activity (BLOK et al., 2013). * Dysregulated cytokines, including keratinocyte-derived chemokine were linked to the poor clinical outcome. (DAMJANOVIC et al., 2013) Toll-like Receptors * Immune mediators play an important role in the pathology of CI through toll-like receptors (METERSKY et al.,2012). * Elevated intrapulmonary levels of toll-like receptors were observed in mice inoculated with CI with an interval of 2 days (METERSKY et al., 2012). * Sustained desensitization of lung sentinel cells to toll-like receptor ligands lasts for several months after cleareance of IV after CI (METERSKY et al., 2012). TLR2 * Mice deficient for TLR2 were colonized to a similar density but transmitted SP more efficiently (100% transmission) than WT animals and showed decreased expression of IFN-α and higher viral titers (RICHARD et al., 2014). * The greater viral burden in TLR2 KO mice correlated with heightened inflammation and was responsible for an increase in bacterial shedding from the mouse nose (RICHARD et al., 2014). IL1RL1/ST2 * Interleukin-1 Receptor Like 1 deficiency did not impact on gross lung pathology in either IV or secondary SP pneumonia (BLOK et al., 2013). UT12 * Survival rates were significantly increased and body weight loss was significantly decreased by UT12 administration (Toll-like receptor 4 agonistic monoclonal Ab UT12) (TANAKA et al.,2013). * The production of inflammatory mediators was significantly suppressed by the administration of UT12. * In a histopathological study, pneumonia in UT12-treated mice was very mild compared to that in control mice (TANAKA et al.,2013). * UT12 increased antimicrobial defense through the acceleration of AM recruitment into the lower respiratory tract induced by c-Jun N-terminal kinase (JNK) and nuclear factor kappaB (NF-kB) pathway-dependent monocyte chemoattractant protein 1 (MCP-1) production (TANAKA et al.,2013). * The study indicates that UT12 promoted pulmonary innate immunity and may reduce the severity of severe pneumonia induced by CI with IV and SP (TANAKA et al.,2013). TLR7 * The pattern-recognition receptor (PRR) toll-like receptor 7 is a major sensor for the viral genome (STEGEMANN-KONISZEWSKI et al., 2013). * In secondary SP infection during acute IV, TLR7 KO mice showed a fatal outcome similar to WT hosts, despite significantly delayed disease progression (STEGEMANN-KONISZEWSKI et al., 2013). * The fatal overall outcome in WT as well as TLR7 KO hosts suggests that processes distinct from TLR7-triggering override the contribution of this single PRR (STEGEMANN-KONISZEWSKI et al., 2013). * Lymphopenia forced by TLR7-triggering did not increase SP-susceptibility or compromise the ability to control SP growth (STEGEMANN et al., 2009).